Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Rebecca Sims, Sven J van der Lee, Adam C Naj, Céline Bellenguez, Nandini Badarinarayan, Johanna Jakobsdottir, Brian W Kunkle, Anne Boland, Rachel Raybould, Joshua C Bis, Eden R Martin, Benjamin Grenier-Boley, Stefanie Heilmann-Heimbach, Vincent Chouraki, Amanda B Kuzma, Kristel Sleegers, Maria Vronskaya, Agustin Ruiz, Robert R Graham, Robert OlasoPer Hoffmann, Megan L Grove, Badri N Vardarajan, Mikko Hiltunen, Markus M Nöthen, Charles C White, Kara L Hamilton-Nelson, Jacques Epelbaum, Wolfgang Maier, Seung-Hoan Choi, Gary W Beecham, Cécile Dulary, Stefan Herms, Albert V Smith, Cory C Funk, Céline Derbois, Davide Seripa, Gianfranco Spalletta, Paola Bossù, Chiara Fenoglio, Maria Serpente, Marina Arcaro, Carlo Caltagirone, Maria Donata Orfei, Antonio Ciaramella, Sandro Sorbi, Paolo Bosco, Daniela Galimberti, Elio Scarpini, Antonio Daniele, ARUK Consortium

Research output: Contribution to journalArticle

Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases= 0.0059, MAFcontrols= 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases= 0.011, MAFcontrols= 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases= 0.0143, MAFcontrols= 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Original languageEnglish
Pages (from-to)1373-1384
Number of pages12
JournalNature Genetics
Volume49
Issue number9
DOIs
Publication statusPublished - Sep 2017

Keywords

  • Adaptor Proteins, Signal Transducing
  • Alzheimer Disease
  • Amino Acid Sequence
  • Case-Control Studies
  • Exome
  • Gene Expression Profiling
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Immunity, Innate
  • Linkage Disequilibrium
  • Membrane Glycoproteins
  • Microglia
  • Odds Ratio
  • Phospholipase C gamma
  • Polymorphism, Single Nucleotide
  • Protein Interaction Maps
  • Receptors, Immunologic
  • Sequence Homology, Amino Acid
  • Journal Article

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  • Cite this

    Sims, R., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., Raybould, R., Bis, J. C., Martin, E. R., Grenier-Boley, B., Heilmann-Heimbach, S., Chouraki, V., Kuzma, A. B., Sleegers, K., Vronskaya, M., Ruiz, A., Graham, R. R., ... ARUK Consortium (2017). Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nature Genetics, 49(9), 1373-1384. https://doi.org/10.1038/ng.3916